Blood contains solutes with different molecular weights: for example, urea has molecular weight 60 Daltons, phosphate has molecular weight 96-97 Daltons, creatinine has molecular weight 113 Daltons, vitamin B12 has molecular weight 1355 Daltons, insulin has molecular weight 5200 Daltons, beta 2-microglobulin has molecular weight 12000 Daltons, and albumin 68000 Daltons.
In the field of dialysis, the first membranes used were highly permeable to small solutes of molecular weight up to 200 Daltons. The clearance of small solutes depends on the permeability and diffusion capacity of the membrane used. The lack of permeability of these membranes for certain medium-sized solutes in the vitamin B12 range (1355 Daltons) was considered as one of the causes determining the occurrence of multiple uremic neuropathies.
To improve the clearance of medium-sized molecules, a first response was to add to the diffusion flow through the membrane a convection flow using high flow membranes with a molecular size cut-off value of 40,000 Daltons. These membranes caused, however, loss of useful plasma constituents such as hormones, vitamins and amino acids.
A further solution for improving clearance of medium-sized molecules is hemofiltration, a purely convective method for the elimination of solutes by the membrane. However, this method extracts a large amount of liquid from blood thereby requiring reinjection of sterile liquid into the blood, and a membrane that is highly permeable to solutes of molecular weight up to 40,000 Daltons. However, in a purely convective mode, the clearance of small-sized molecules is poor.
A further method where hemofiltration and hemodialysis were combined is known as haemo-diafiltration. However, problems that arise include difficulty in precisely controlling the haemo-filtration flow, high loss of hormones and amino acids, the complexity of the system, the large quantities of sterile liquid and dialysate necessary, and consequently the high cost of the treatment. In order to offer a better solution capable of clearance of more selective clearance of blood solutions have been conceived using two or more filtration units.
For instance, U.S. Pat. No. 6,193,681 describes an apparatus to treat septicaemia in the blood. The blood flows first through a UV irradiation device and then through a blood concentrator before re-injection in the patient. A secondary circuit is connected to a second outlet from the blood concentrator from which the fluid flows out through a filter followed by a membrane module and a dilution source, and is then injected upstream of the blood concentrator.
Furthermore, US2004182787 discloses a system combining two or more filtration units where the fluid ultrafiltered through a first treatment unit is treated by a second unit before being re-injected in the extracorporeal blood circuit. This solution offered good clearance, while consuming small amounts of sterile liquid.
As used herein, the expression “cut-off” refers to the Molecular Weight Cut Off (MWCO) which is measured in Dalton. The MWCO is defined as the minimal molecular weight of a globular molecule which is retained by the membrane to at least about 90%.
As used herein the expression “small-sized molecules” refers to molecules of molecular weight less than about 2000 Daltons.
As used herein, the expression “medium-sized molecules” refers to molecules of molecular weight between about 2000 Daltons and about 50,000 Daltons. Among medium sized molecules the following subgroups can be identified: “small middle molecules” refers to molecules with size in the range from about 5000 Daltons to about 30,000 Daltons and “large middle molecules” refers to molecules with size in the range from 30,000 Daltons to 50,000 Daltons.
As used herein, “large-sized molecules” refers to molecules of molecular weight greater than about 50,000 Daltons (for example, proteins).